Thursday, January 27

Ketones fuel fetal development

Ketosis during pregnancy has been known for many years. Fetal growth depends on constant energy supply, so physiological mechanisms should have been developed during evolution to assure intra-uterine development under starvation or food scarcity. Most studies focusing on pregnancy and fetal development have been done, for obvious reasons, on animals. It is not possible to extrapolate every detail, but it gives us a great idea and explanation for the metabolic changes observed during pregnancy. 

Briefly, there are two metabolic periods clearly differentiated during gestation. The first one, corresponding to the first two thirds, is the anabolic phase characterized by hyperphagia and enhanced storage of body fat (we will call it Phase I). During the last third of gestation, the catabolic phase, fetal growth is very rapid, so the energy needs of the fetus are increased (1) (we will call it Phase II). Insulin metabolism, as an acquired evolutionary mechanism, plays a key role during this process. During Phase I, there is a 3.0 to 3.5 fold increase in first-phase and second-phase insulin release in response to glucose, without an alteration in peripheral IS (2). This assures that accumulation of protein, glucose and fat is appropriate for late pregnancy.  As pregnancy progresses, this increase in glucose-stimulated insulin secretion is maintained, but IS is reduced in 50-70% (34) during late pregnancy (Phase II). This mechanism serves to redistribute glucose and energy to the rapid growing fetus. In addition to peripheral IR (but not hepatic), gluconeogenesis (GnG) is increased 16 to 30% to supply the placenta and fetus demand. Contrary to the main GnG precursors in non-pregnant adults, glycerol is the main glucose precursor, which represents a mechanism by which in the abscence of food, the mother is capable of producing the necessary glucose from a substrate that is readily available during fasting and not depend on external substrates. This process is accentuated by fasting, commonly known as "accelerated starvation": compared to non-pregnant, women during gestation exhibit a pronounced hypoglycemia and rapid rise in KB. GnG increases parallels the rise in KB (4). Because of its increased utilization, glucose has drawn much attention away from the importance of KB in fetal development. 

bOHB is utilized in a dose-dependent manner by the rat conceptus (5) and serves to spare glucose and lactate for biosynthetic pathways (6). bOHB seems to be the main oxidative fuel to the human fetal brain, measured by the production of CO2 (7). A classic study done on rat embryos underscore the importance of both glucose and bOHB to a proper development (8). Researchers tested the effect of increasing doses of glucose, KB or both on organ teratogenesis. They first tested glucose alone. According to the authors:
(...) we found that isosmotic supplementation of the culture medium with 12 mg/mL D-glucose during the 48-h incubations effected a generalized retardation of rat-embryo growth and lesions such as microencephaly, exencephaly, open neural tube, and pericardial edema (6). We documented specificity by demonstrating that the findings are not replicated with isosmotic equimolar additions of certain other hexoses, such as sorbitol, fructose, inositol, or galactose (6). Teratogenic potentialities of high glucose concentrations have also been demonstrated with cultured mouse embryos. Sadler elicited dysmorphogenic effects with increasing frequency by adding 5mg/mL or 8 mg/mL D-glucose to the suspending rat serum during mouse-embryo culture (33).
So high glucose concentrations are teratogenic for the embryo. They went further and examinated the effect of increasing doses. 
During the period of these studies in 1980-1981, isosmotic additions of 12 mg/ mL elicited a 49% incidence of minor and a 23% incidence of major lesions. By contrast isosmotic additions of 3 mg/mL D-glucose to the incubation medium did not evoke any discernible lesions during 48 h of culture, 6mg/mL resulted in only a 2.2% incidence of minor and no major lesions, and 9 mg/mL D glucose were required to elicit 5.1% major and 17.8% minor lesions in the cultured intact embryos from our outbred strain of Charles River Sprague-Dawley rats.
They concluded:
(...) the dysmorphogenic potentialities of ambient glucose are clearly concentration dependent although the precise relationships may be quantitatively different in various species or in different strains from the same species.
So we know that hyperglicemia is teratogenic. But what about increasing doses of bOHB? 
Preliminary acute incubations with 14C-labelled 14C-hydroxybutyrate indicated that cultured embryo units can oxidize ketones on day 10.4 as well as 1 1.4 of development (36) so that ketones can subserve nutrient functions in some portions of the conceptus at both times. What about the effects of ketones on embryogenesis during these intervals? As summarized in Figure 3, isosmotic additions of 2 or 4 mM buffered D,L sodium (3-hydroxybutyrate during 48-h culture of rat conceptus from day 9.5 to 1 1 .5 of development did not elicit any discernible dysmorphogenesis.
So physiological concentrations of bOHB, as in a low carbohydrate diet, ARE NOT TERATOGENIC. Problems appear only when going above this threshold, as in DK. 
However, with 8 mM, 24.5% of the embryos developed minor lesions, and the inclusion of 16 mM D,L /3-hydroxybutyrate was associated with a 71% frequency of minor and 45% incidence of major lesions (36). 
See the trend? With 8mM only a quarter developed minor lesions. But when levels went way up (not physiological) lesions are aggraviated.

On the left, added concentrations of glucose and on the right, added concentrations of bOHB. The trend is clear, there is no damage when KB are in the physiological range, but when levels increase to concentrations seen in DK, boom! As always, the problem arises with hyperketonemia, not ketosis. Its easier to develop hyperglycemia than hyperketonemia (except during starvation).

Lastly, what happens if we mix the minimally teratogenic amount of glucose (6mg/dL) with the minimally teratogenic amount of bOHB (8mM)? Sinergy! 66% displayed minor lesions and 27.7% major lesions. Some of the effects could not be explained by normal growth retardation. 

KB are so important to normal growth that there is evidence that fetal ketogenesis occurs (9). To achieve an optimal development, the fetus must not be exposed to increased concentrations of KB nor glucose. Both sources of fuel are necessary but in the right amount. The body adapts to this situation increasing the production of glucose from glycerol, reducing the need for ingesting extra glucose. Increasing calories and carbohydrates during pregnancy predisposes the mother to hyperglycemia, GD and IR, neonatal macrosomy and teratogenesis. Reducing the GL of the diet has shown to offer benefits compared to a low-fat diet (10), even when carbohydrate intake is reduced to 40-45% of total calories (11). Controlled studies adressing the effects of less than 40% of carbohydrates are scarce (evil ketosis!). Nevertheless, going zero carb can be as dangerous as going high carb* (12). But there is no need to go up to 60%. In rats, the requirement for normal growth seems to be around 18-20% (13), comparable amount of carbohydrates eaten by most low carbers and/or paleo, while the human fetus consumes around 20-25g/glucose per day during late gestation (4)

Maintaining a proper diet with plenty of saturated fat, low carbohydrate and adequate protein/EPA+DHA is essential for a healthy pregnancy. Quality over quantity.

Any experiences to share?

*Although this is physiolgically impossible. Only achievable eating zero carb protein drinks and oil.


  1. i agree ketosis is kinda a given in pregnancy, very thorough post here! do you have an opinion on fertility in conceiving? ketogenic diet doesnt seem like it would affect fertility but i also have no gained back my fertility regardless of being in ketosis vs not, wondering if you have an opinion.

    cant wait for your blog to get some attention and commenters im gonna get the word out!!

  2. @Malibu:

    Thank you for your kind words. Im trying to do my best to reinvigorate ketones. Regarding fertility, I think it depends on the origin and the time being infertile. Just like a diabetic, some get completely cured after a KD, some only reduce their meds. The raw material necessary is protein + saturated fat and cholesterol (animal food), not sure about ketones per se (probably have a role as oxidative fuel).

  3. Brilliant post, Lucas. Thanks so much for your time and attention to detail on this critical topic.

  4. @cillakat: Thank you!

  5. @Malibu, I would supsect it also would vary depending on the cause of the infertility - ie PCOS v. gluten intolerance. (though I realize there is much correlation...) For some, just improving nutrient density will be sufficient.

  6. Great new low carb blog.I bookmarked as it will be one to watch.Lucas,any chance of doing some posts on glycation?

  7. @Wolfstriked:

    Thank you. Some glycation stuff will definately be posted.

  8. Fascinating and timely post -- for me. I've been paleo since last September, but throughout the fall was also on fertility treatments, so the extra fat I was carrying did not melt off me as it was doing from my paleo pal DH. Once I got pregnant, I began to lose weight. I am eating plenty of high quality animal fats and coconut oil and am still losing weight now, at 5 months along, while the baby is of optimal growth and weight.

    The problem is the doctor, who was freaking out at my 7 lb weight loss this last month. But we feel my diet is pure and excellent, so we won't let the traditional medical view affect us.

    However, I was worried that if perchance I was ketonic, would this be somehow bad for the baby's development. Your post is a huge relief, thanks.

  9. Christine

    Interesting post - a bit of fresh air in all that negativity surrounding ketosis in pregnancy! I'm almost 5 months pregnant, on a basically "zero carb" diet. I still had a lot of weight to lose when I became pregnant, and I lost almost 30 pounds in the first three months. My weight is now stable, while the baby is growing normally... Of course the docs freaked out, some said it was "my choice" but that they weren't sure I wasn't harming my baby... (so you mean all Inuit babies MUST be retarded, right?? :-))

    I'm also Type 2 diabetic and my blood sugar levels are good and very stable too, so the specialist who was screaming for insulin AND meds 2 months ago now doesn't even mention them anymore, duh!

    I get tested every month for ketones and it's always positive, but not even to the maximum. But then the specialist has never said anything about the level of ketones...

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